Project Summary Sickle cell disease (SCD) causes vision-threatening ocular complications such as proliferative retinopathy. Risk of sickle cell retinopathy increases with age, with some reports showing >60% of SCD patients having proliferative retinopathy after age 40. It remains unclear how sickle cell trait (SCT), the heterozygous genotype with one copy of the sickle cell mutation, may affect the eye. SCT, albeit assumed mild, is prevalent and chronic. It affects 3 million Americans including ~8-10% of African Americans. It is known that under conditions of stress or concomitant systemic diseases, SCT can become a pathologic risk factor for retinopathy. Evidence has been accumulating to support that SCT can increase the risk of venous thromboembolism, ischemic stroke, and glomerulopathy - conditions that have all been linked to an increased risk of retinopathy. These findings, together with the increasing recognition of the role of ocular hemodynamics in various ocular diseases, support a possible association between SCT and eye diseases/conditions. Because individuals with SCT have a normal life expectancy, their vascular bed may accumulate damages from SCT as a result of repeated insults over a long duration. We hypothesize that older individuals with SCT have an increased risk of eye diseases, either alone or in conjunction with other known ocular risk factors (e.g., hypertension, diabetes). To test this hypothesis, we propose an investigation nested within the African American Eye Disease Study (AFEDS), an ongoing population-based study of 6,000 African Americans aged 40 years and older that has collected a large amount of epidemiological, biological, and ocular data and biospecimens. Taking advantages of the unique, existing resources of AFEDS, we propose to 1) identify the SCT status of 2,700 AFEDS participants who donated samples of blood and retrospectively examine the associations between SCT and risk of ocular diseases/conditions, and 2) acquire additional imaging data from ~216 individuals with SCT (432 eyes) using advanced technologies (e.g. optical coherence tomography angiography, enhanced depth imaging of the choroid, ultra-wide imaging of the retina, and conjunctival microcirculation imaging) and assess changes in ocular structure, retinal microvasculature, and conjunctival hemodynamics due to SCT. As SCT is now routinely detected in all US newborns and little is known about ocular complications associated with SCT, our population-based study will fill an important knowledge gap. This timely investigation will provide valuable, new data on how long-term exposure to SCT and associated vaso-occlusive events and hemolysis can alter ocular microcirculation and structure. It will also inform us about how these events can contribute to vasculopathy in other organs that share similar anatomical and physiologic properties with the eyes. Such knowledge will be important contributors to the ongoing debate on health risk associated with SCT, and will help clinicians, public health professionals, and policy experts allocate targeted healthcare and counseling services.